1. Field of the Invention
The present disclosure relates to novel use of angiogenin for treatment of corneal endothelial wounds.
2. Description of the Related Art
Human corneal endothelial cells organize a physiologically most important single cell layer that maintains corneal transparency by controlling moisture movement based on dynamic equilibrium between leaky barrier functions and active pumping actions. However, the corneal endothelial cells that are damaged in vivo are extremely limited for regeneration. Thus, when the endothelial cells are damaged by several diseases such as Fuchs' dystrophy, wounds, pseudophakic bullous keratopathy, or the like, the endothelial cells may cause corneal edema and opacity and accordingly, may result in severe loss of sight.
These human corneal endothelial cells are quiescent in the G1 phase of the cell cycle throughout their lifetime, and at the same time, may be able to heal damaged areas by increased cell migration and cell size, whereas most cells are associated with cell proliferation and migration in the process of wound healing due to increased expression of a number of regulators such as a p53 gene that inhibits the cell cycle progression. The human corneal endothelial cells do not proliferate by cell division, but according to the recently published reports, it is reported that there are sites for the centripetal proliferation and migration of endothelial cells from the corneal endothelial periphery present around the extreme periphery of corneal endothelium (He Z, & Campolmi N, & Gain P, & Ha Thi BM, & Dumollard J M, & Duband S, & Peoc'h M, & Piselli S, & Garraud O, & Thuret G. Revisited microanatomy of the corneal endothelial periphery: new evidence for continuous centripetal migration of endothelial cells in humans. Stem Cells. 2012; 30:2523-2534).
Angiogenin is a 14.4-kDa single chain protein of 123 amino acids, and is one of secreted proteins capable of inducing angiogenesis along with a vascular endothelial growth factor (VEFG). In regard to mechanisms for proliferation of the endothelial cells upon angiogenesis, it is known that the PI3k-Akt-endothelial nitric oxide synthase (eNOS) pathway and the extracellular signal-regulated kinase (Erk) pathway become activated and nitric oxide (NO) induced by the eNOS may prevent apoptosis of the vascular endothelial cells and enhance migration thereof.
It is found that the flow of aqueous humor in the eyes has a similar shearing force with that of the blood flow which is regarded as a stimulatory factor for proliferation of the vascular endothelial cells and is directly adjacent to the corneal endothelial cells, and that the angiogenin-associated pathway in the vascular endothelial cells is significantly similar to the survival pathway of the human corneal endothelial cells. In this regard, angiogenin is configured to be used for treatment of corneal endothelium wounds.
Angiogenin described herein is a material that is not much researched in the field of ophthalmology yet. However, according to Korean Patent Application No. 10-2013-0037477, angiogenin is disclosed as a composition for preventing or treating inflammatory disease, and the disclosed invention describes that ocular disease is associated with anti-immune therapy for preventing or treating decreased visual acuity, which is caused by angiogenesis and opacification of the corneal stroma due to chronic ocular inflammation and immune response by cataract, glaucoma, eye injury or the like. Meanwhile, the disclosure of the present invention is configured to activate the PI3k-Akt-eNOS pathway of angiogenin in the corneal endothelial cells that are not capable of self-proliferation, wherein angiogenin is identified to be effective in promoting healing of the human corneal endothelium wounds.